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A Phase III Intergroup CLL Study of Asymptomatic Patients With Untreated Chronic Lymphocytic Leukemia Randomized to Early Intervention Versus Observation With Later Treatment in the High Risk Genetic Subset With IGVH Unmutated Disease

Trial Information

A Phase III Intergroup CLL Study of Asymptomatic Patients With Untreated Chronic Lymphocytic Leukemia Randomized to Early Intervention Versus Observation With Later Treatment in the High Risk Genetic Subset With IGVH Unmutated Disease

OBJECTIVES:

Primary

- To determine if early treatment with chemoimmunotherapy comprising fludarabine
phosphate and rituximab extends the time to second treatment in patients with
genetically high-risk (unmutated IgV_H), asymptomatic, previously untreated chronic
lymphocytic leukemia (CLL).

- To determine the time to disease progression that would warrant second treatment.

- To determine overall survival.

Secondary

- To measure the proportion of patients with asymptomatic, previously untreated CLL who
have mutated and unmutated IgV_H genes.

- To determine the differences in acute and chronic toxicity of administering
chemoimmunotherapy early to patients with genetically high-risk CLL compared to waiting
until symptoms develop.

- To determine the effect of select pretreatment clinical and biological characteristics
(such as interphase cytogenetic abnormalities, ZAP-70 expression, and p53 dysfunction
[primary and secondary]) on response, time to second treatment, and overall survival of
patients with genetically high-risk CLL randomized to early treatment.

- To determine the effect of select pretreatment clinical and biological characteristics
(such as interphase cytogenetic abnormalities, ZAP-70 expression, and p53 dysfunction)
on response, time to first and second treatments, and overall survival of patients with
genetically high-risk CLL randomized to standard treatment (observation until symptoms
occur).

- To describe the natural history of patients with genetically low-risk (mutated IgV_H
genes), asymptomatic, previously untreated CLL, in terms of time to initial treatment,
response, progression, and survival.

- To determine the effect of select pretreatment characteristics on time to first
treatment, response, progression, and survival of patients with genetically low-risk
CLL.

- To determine whether highly sensitive flow cytometry negativity at completion of
therapy in patients randomized to early treatment is an effective surrogate marker for
prolonged time to second treatment, overall survival, and other clinical benefits.

- To collect demographic data on familial CLL in newly diagnosed patients participating
on this study.

OUTLINE: This is a multicenter study.

- Genetically high-risk disease: Patients are stratified according to age (< 50 years vs
50 to 70 years vs > 70 years) and presence of the high-risk genetic feature
[del(11)(q22.3) or del(17)(p13.1)] by FISH (yes vs no). Patients are randomized to 1 of
2 treatment arms.

- Arm I: Patients receive rituximab IV over 4 hours on days 1, 3, and 5 of week 1
and then on day 1 of weeks 5, 9, 13, 17, and 21. Patients also receive fludarabine
phosphate IV over 30 minutes on days 1-5 of weeks 1, 5, 9, 13, 17, and 21. After
completion of chemoimmunotherapy, patients are followed every 3 months until
disease progression. At the time of disease progression, patients receive
retreatment with chemoimmunotherapy as above or another treatment regimen.

- Arm II: Patients are followed every 3 months until disease progression. At the
time of disease progression, patients receive rituximab and fludarabine phosphate
as in arm I. Patients are then followed every 3 months until second disease
progression. Patients with a second disease progression receive retreatment with
chemoimmunotherapy as above or another treatment regimen.

- Genetically low-risk disease: Patients are followed every 3 months until disease
progression. At the time of disease progression, patients receive rituximab and
fludarabine phosphate as in arm I. Patients are then followed every 3 months until
second disease progression. Patients with a second disease progression receive
retreatment with chemoimmunotherapy as above or another treatment regimen.

- Local institution lymphocyte phenotype must reveal a predominant B-cell
monoclonal population sharing a B-cell marker (CD19, CD20, CD23) with the CD5
antigen, in the absence of other pan-T-cell markers

- B-cells must be monoclonal with regard to expression of either κ or λ and
have surface immunoglobulin expression of low density

- Patients with bright surface immunoglobulin levels must have CD23
coexpression and absence of t(11;14) on interphase cytogenetics or have
negative tumor protein staining for cyclin D1

- Low-risk category (i.e., only stages 0 or I) of the modified three-stage Rai staging
system

- No evidence of active or progressive disease as demonstrated by any of the following:

- Must have undergone IgV_H mutation testing and be classified according to the
following:

- Genetically low-risk disease

- IgV_H mutated

- Less than 98% IgV_H homology

- Genetically high-risk disease

- IgV_H unmutated

- At least 98% IgV_H homology

PATIENT CHARACTERISTICS:

- Performance status 0-1

- Creatinine ≤ 1.5 times upper limit of normal

- No HIV disease

- Not pregnant or nursing

- Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

- No prior therapy for CLL, including corticosteroids for autoimmune complications that
have developed since the initial diagnosis of CLL

- No concurrent hormones or other chemotherapy except for steroids for hypersensitivity
reactions or new adrenal failure (chronic requirement for steroids is an exclusion
criterion for this study) or hormones for non-disease-related conditions (e.g.,
insulin for diabetes)

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